JP2003137781A - Ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To reduce the disagreeable feeling of an ophthalmic composition in the case of applying the composition to the ophthalmic mucosa. SOLUTION: Disagreeable feeling of an ophthalmic composition such as stimulation to the eye, pain of the eye and disagreeable taste caused by the application of the composition to the ophthalmic mucosa can be reduced by adding a xanthine compound (caffeine, theophylline, theobromine, proxyphylline, pentoxyphylline, or the like) to the composition. Ophthalmic compositions having excellent feeling in use such as eye drop, eye wash and contact lens solution can be produced by the method to improve the compliance of the user.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an ophthalmic composition having an improved unpleasant feeling when applied to the ocular mucosa.

[0002]

2. Description of the Related Art People who use eye drops feel various feelings when they are applied to the mucous membrane of the eyes, such as the degree of eye irritation, the feeling of cooling and cooling, the feeling of moistness and the feeling of stickiness. A comprehensive evaluation is performed to judge the "comfort" and a more desirable "comfort" is desired. This comprehensive evaluation of the feeling of use, also called "comfort," is an important issue peculiar to ophthalmic compositions, and the good or bad of "comfort" has a significant effect on the compliance of the user. Comfort "
Designing a drug product with the goal of

The "comfort" felt by the user mainly depends on the eye irritation at the time of application. Furthermore, the eye has a structure in which the mucous membrane of the eye such as the cornea and conjunctiva is exposed on the surface, and it is an organ that responds to physical stimuli and chemical stimuli such as drugs with extremely high sensitivity. Responds strongly and sensitively to even slight stimuli. Therefore, for ophthalmic compositions such as eye drops and contact lens solutions that are in direct contact with the eye, eye wash, eye ointment and the like, it is necessary to study the formulation paying sufficient attention to irritation to the eye, Therefore, it is important to improve the "feeling of comfort" felt by the user.

Further, the preparation applied to the ocular mucosa is left undiluted or diluted with lacrimal fluid, is aspirated from the punctum and moves from the nasolacrimal duct into the nasal cavity, and then into the oral cavity. Therefore, the user does not directly apply the components contained in the preparation to the oral cavity, but feels an unpleasant taste or odor such as a bitter component, an astringent taste, an astringent taste, and a sweet taste after application to the ocular mucosa. Such an unpleasant feeling of use such as taste and odor after application to the ocular mucosa causes hesitation in the use of ophthalmic compositions such as eye drops, and eventually reduces the compliance of the user. Therefore, it is important to improve the feeling of use by alleviating the unpleasant taste caused by the components added to the ophthalmic composition.

By the way, cromoglycic acid, acitazanolast, levocabastine, emedastine, epsilon-aminocaproic acid, or salts thereof, which are compounds commonly used in ophthalmic compositions, cause unpleasant eye irritation and eye pain when applied to the ocular mucosa. Was a problem. Further, berberine, glycyrrhizinic acid or salts thereof has a problem that they have an unpleasant taste when applied to the ocular mucosa. These compounds have a useful pharmacological action, and although they exert an excellent effect when applied to the ocular mucous membrane, they have a problem of causing an unpleasant feeling of use, which in turn leads to user compliance. Lowers. Therefore, there has been a demand for a method of improving the unpleasant feeling of use when an ophthalmic composition containing these compounds is applied to the ocular mucosa.

[0006]

In view of the above problems, an object of the present invention is to provide an ophthalmic composition containing cromoglicic acid, acitazanolast, levocabastine, emedastine, epsilon-aminocaproic acid, berberine, glycyrrhizic acid or a salt thereof. It is to provide a method of improving the "comfort", that is, the feeling of use. Then, the present invention is to provide an ophthalmic composition having an improved feeling of use by using such a method.

[0007]

Means for Solving the Problems As a result of intensive studies for achieving the above object, the present inventors have found that a compound of the formula (1) or a salt thereof and cromoglic acid, acitazanolast, levocabastine, emedastine, epsilon- It was found that an ophthalmic composition containing aminocaproic acid, berberine, glycyrrhizic acid or a salt thereof achieves the above-mentioned object, and has completed the present invention.

That is, the present invention provides the following (I) to (IV)
An ophthalmic composition listed in: (I) i) Formula (1)

[Chemical 2] (Wherein R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group) or a pharmaceutically acceptable compound thereof. At least one compound selected from the following salts, and ii) cromoglicic acid, acitazanolast, levocabastine, emedastine, epsilon-aminocaproic acid,
An ophthalmic composition comprising at least one compound selected from berberine, glycyrrhizic acid or a pharmacologically acceptable salt thereof, (II)
The compound of formula (1) described in (I) is caffeine, pentoxifylline, theophylline, diprophylline, theobromine, proxyfilin, the ophthalmic composition according to (I), (III) cromoglycic acid, acitazano Last, emedastine, epsilon-aminocaproic acid,
At least one compound 1 selected from berberine, glycyrrhizic acid or a pharmacologically acceptable salt thereof 1
The ophthalmic composition according to (I) or (II), wherein 0.1 part by weight or more of the compound represented by formula (1) or a salt thereof described in (I) is blended with respect to parts by weight. , (IV)
Levocabastine or a pharmacologically acceptable salt thereof 1
The ophthalmic composition according to (I) or (II), wherein 4 parts by weight or more of the compound represented by formula (1) or the salt thereof described in (I) is blended with respect to parts by weight.

Further, the present invention is a method for improving the following feelings of use: (V) Cromoglic acid, acitazanolast, levocabastine, emedastine, epsilon-aminocaproic acid, berberine, glycyrrhizic acid or pharmacologically thereof. An ophthalmic composition containing at least one compound selected from an acceptable salt is represented by the formula (1) according to (I):
A method for improving the feeling of use of the ophthalmic composition by blending the compound represented by: or a pharmaceutically acceptable salt thereof. In this specification,% means w / v% unless otherwise specified. Further, in the present specification, the contact lens is meant to include all types of contact lenses such as hard, oxygen permeable hard, and soft.

[0010]

DETAILED DESCRIPTION OF THE INVENTION In the compound represented by the formula (1), the alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, C _1-6 alkyl group such as a t- butyl group (especially C _1-4 alkyl group)
Can be illustrated. Preferred alkyl groups include methyl and ethyl groups.

These alkyl groups are substituted, for example, by
Halogen atom (chlorine, bromine, fluorine atom, etc.), hydroxyl group, alkoxy group (C _1-4 alkoxy group such as methoxy, ethoxy, butoxy group), aryloxy group, carboxyl group, alkoxycarbonyl group (C
_C1-4 alkoxy - carbonyl group), an aryloxycarbonyl group, an acyl group (formyl, acetyl, C _1-4 alkyl, such as propionyl group - carbonyl group, an aryl such as benzoyl group - carbonyl group), a nitro group, an amino Group, N-substituted amino group (mono or di C
_1-4 alkylamino group), a cyano group and the like.

The compound represented by the above formula (1) can be used as a pharmacologically (pharmaceutically) or physiologically acceptable salt. As the pharmacologically or physiologically acceptable salt,
For example, organic acid salts (eg, lactate, acetate, butyric acid, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate, malonate, methanesulfonate, toluene). Sulfonate, tosylate, palmitic acid, stearic acid, etc.), inorganic acid salt (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.),
Salts with organic bases (for example, methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, amino acids, salts with organic amines such as tripyridine and picoline), salts with inorganic bases (for example, ammonium salt, sodium) , An alkali metal such as potassium, an alkaline earth metal such as calcium and magnesium, a salt with a metal such as aluminum), and the like.

Specific compounds represented by the above formula (1) include, for example, caffeine, theophylline, oxtriphylline, daphylline, diisobutylaminobenzoyloxypropyl theophylline, theobromine, diprophylline, proxyphylline, pentoxifylline and the like. Is mentioned. Preferred compounds are caffeine, theophylline, theobromine, diprophylline, proxyphylline, pentoxifylline, etc., and caffeine is particularly preferable. Caffeine also includes anhydrous caffeine.

These compounds represented by the above formula (1) or salts thereof (hereinafter, they may be collectively referred to as "xanthines") may be used alone or in combination of two or more kinds.

Further, the compound represented by the above formula (1) can be used in the form of a mixture with other compounds. Examples of such a mixture include, for example, sodium caffeine benzoate, which is a mixture of caffeine and sodium benzoate, caffeine citrate, which is a mixture of caffeine and citric acid, and a mixture of theophylline and ethylenediamine. Examples include aminophylline, bufilin, which is a mixture of theophylline and aminoisobutanol, calcium theobromine salicylate, which is a mixture of theobromine and salicylate, sodium theobromine salicylate, and sodium theobromine acetate, which is a mixture of theobromine and sodium acetate.

The amount of the xanthines used in the ophthalmic composition of the present invention varies depending on the kind of the compound represented by the above formula (1) and cannot be unconditionally specified, but it is usually in the ophthalmic composition. The concentration of the compound represented by the formula (1) or a salt thereof can be selected from the range of about 0.000001 to 20%, preferably 0.0001 to 10%, more preferably 0.01 to 5 (for example, , 0.05 to 4%), and more preferably about 0.1 to 3%.

In the present invention, cromoglycic acid, acitazanolast, levocabastine, emedastine, epsilon-aminocaproic acid, berberine, glycyrrhizic acid or a pharmacologically acceptable salt thereof (hereinafter, these are collectively referred to as uncomfortable feeling It may also be referred to as a component that has.
Examples of the salt include the same salts as those described for the compound of the formula (1), for example, sodium cromoglycate,
Examples include emedastine fumarate, berberine sulfate, berberine chloride, levocabastine hydrochloride, dipotassium glycyrrhizinate, and trisodium glycyrrhizinate, which may be used in the form of hydrates. These can be produced by known methods, or commercially available products may be used. In addition, one or more of these may be used in the ophthalmic composition.

The amount of cromoglycic acid, acitazanolast, levocabastine, emedastine, epsilon-aminocaproic acid, berberine, glycyrrhizic acid or a salt thereof in the ophthalmic composition of the present invention used in the ophthalmic composition is cromoglic acid or In the case of the salt, for example, if the ophthalmic composition is an eye drop, the dosage can be appropriately designed to be 0.04 μg to 40 mg as a daily application amount. The concentration is 0.0001 to 20%, preferably 0.0001 to 15
%, More preferably 0.001 to 10%, and particularly preferably 0.01 to 5%. In the case of acitazanolast, for example, when the ophthalmic composition is an eye drop, the daily dose is 0.1%. The formulation can be appropriately designed to be 0004 μg to 20 mg, and the concentration in the ophthalmic composition is usually 0.00001 to 10%, preferably 0.0000.
1 to 5%, more preferably 0.0001 to 1%, particularly preferably 0.0005 to 0.5%. In the case of levocabastine or a salt thereof, for example, if the ophthalmic composition is an eye drop, daily administration As amount, 0.00004μg-3mg
It is possible to appropriately design the formulation so that the concentration in the ophthalmic composition is 0.0000001 to 1.
5%, preferably 0.000001 to 0.5%, more preferably 0.00001 to 0.1%, particularly preferably 0.0001 to 0.05%, in the case of emedastine or a salt thereof, for example, for ophthalmic use If the composition is an eye drop, it is possible to appropriately design the formulation such that the daily dose is 0.0004 μg to 30 mg, and the concentration in the ophthalmic composition is usually 0.00001 to 5%. ,Preferably,
0.0001 to 1%, particularly preferably 0.001 to 0.
In the case of 5% epsilon-aminocaproic acid or a salt thereof, for example, if the ophthalmic composition is an eye drop, it is possible to appropriately design the formulation so that the daily dose is 0.04 μg to 30 mg. , The concentration in the ophthalmic composition is 0.0001 to 15%, preferably 0.001 to 15%
%, More preferably 0.01 to 10%, particularly preferably 0.05 to 5%, in the case of berberine or a salt thereof,
For example, if the ophthalmic composition is an eye drop, it is possible to appropriately design the formulation such that the daily dose is 0.004 μg to 10 mg, and the concentration in the ophthalmic composition is 0.00001 to 5%, preferably 0.00001-1
%, More preferably 0.0001 to 0.1%, particularly preferably 0.0003 to 0.03%, in the case of glycyrrhizic acid or a salt thereof, if the ophthalmic composition is an eye drop, the daily dose Can be appropriately designed to be 0.004 μg to 20 mg, and the concentration in the ophthalmic composition is 0.00001 to 10%, preferably 0.0001 to 3%, more preferably 0. 0.001-
1%, particularly preferably 0.005-0.5%.

The mixing ratio of the xanthines and the component having an unpleasant feeling of use in the ophthalmic composition varies depending on the kind of the compound. It is preferable to mix it in a proportion of 1 part by weight or more. In the case of chromoglicic acid, acitazanolast, emedastine, epsilon-aminocaproic acid, glycyrrhizinic acid, berberine or its salts, xanthines should be blended in a ratio of 0.1 parts by weight or more to 1 part by weight of these components. Can further improve the unpleasant feeling of use. In the case of levocabastine or a salt thereof, when the xanthines are mixed in a proportion of 4 parts by weight or more with respect to 1 part by weight of this component, the unpleasant feeling of use can be further improved. The effect of the present invention can be obtained by blending the xanthines in the above proportions or more, but from the viewpoint of safety, 1000 parts by weight of the xanthines are usually added to 1 part by weight of the component having an unpleasant feeling of use. The following, preferably 500 parts by weight or less, more preferably 1
It may be added in an amount of 00 parts by weight or less, particularly preferably 50 parts by weight or less.

The ophthalmic composition of the present invention is used to treat unpleasant eye irritation such as cromoglycic acid, acitazanolast, levocabastine, emedastine, epsilon-aminocaproic acid, berberine, glycyrrhizic acid or salts thereof when applied to the ocular mucosa. Even if the composition contains a component having an unpleasant feeling of use such as eye pain or unpleasant taste, the unpleasant feeling of use can be improved by incorporating the xanthines. The ophthalmic composition containing the component having an unpleasant feeling of use of the present invention improves the user's compliance and improves the feeling of use. Therefore, as long as it utilizes such an effect, its intended use is not specified, and it can be used in various fields such as pharmaceuticals and quasi drugs.

The ophthalmic composition of the present invention can be provided in various forms depending on the purpose.

Examples of the ophthalmic composition of the present invention include:
Eye drops (including eye drops that can also be used while wearing contact lenses (CL)), eye washes (including eye drops that can be used while wearing contact lenses (CL)), eye ointments , Contact lens (CL) mounting solution,
Examples include agents for contact lenses (CL) (cleaning solution, preservative solution, sterilizing solution, multipurpose solution, etc.). Among them, it is useful as an ophthalmic solution such as eye drops, eye washes, and contact lens preparations in which the formulation spreads on the ocular surface immediately after application.

By adding a cooling component to the ophthalmic composition of the present invention, the feeling of use can be improved and the compliance can be remarkably increased. Such a cooling component is a component capable of imparting a refreshing sensation, and examples thereof include essential oils and / or essential oil components. In particular,
Essential oils such as fennel oil, eucalyptus oil, bergamot oil, peppermint oil, rose oil, peppermint oil, cool mint oil, cinnamon oil and essential oil components such as camphor, borneol, geraniol, menthol, citroneol and limonene (especially terpenes) Is mentioned. These are 1
These can be added as appropriate, or two or more types can be combined, and any of d, l, and dl forms can be used.
Preferred cooling components include menthols (1-menthol, d-menthol, dl-menthol, etc.), camphors (d-camphor, dl-camphor, etc.), borneols (d-borneol, dl-borneol, etc.), geraniol. And essential oils containing many of these components (mint oil, peppermint oil, eucalyptus oil, etc.).

When a cooling component is further added to the ophthalmic composition, the feeling of use can be further improved by blending the cooling component in a concentration such that the cooling component itself does not cause eye irritation. ~ 1.0%, preferably 0.0
005-0.5%, more preferably 0.001-0.
It is 1%, especially 0.01 to 0.05%.

In addition, it is preferable to add a surfactant to the ophthalmic composition in order to improve the solubility of each component and further enhance the feeling of use. Examples of such a surfactant include polyoxyethylene (POE) -polyoxypropylene (POP) block copolymers (for example, poloxamer 407, poloxamer 235, poloxamer 188, etc.), monolauric acid POE.
(20) POE sorbitan fatty acid esters such as sorbitan (polysorbate 20) and POE monooleate (20) sorbitan (polysorbate 80), P
POE hydrogenated castor oil, such as OE (60) hydrogenated castor oil,
POE (9) POE alkyl ethers such as lauryl ether, POE (20) POP (4) POE / POP alkyl ethers such as cetyl ether, POE
(10) Nonionic surfactants such as POE alkylphenyl ethers such as nonylphenyl ether; glycine type such as alkyldiaminoethylglycine; betaine acetate type such as lauryldimethylaminoacetic acid betaine;
Amphoteric surfactants such as imidazoline type; POE (10)
POE alkyl ether phosphates such as sodium lauryl ether phosphate and salts thereof, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, N-acyl taurine salts such as N-cocoylmethyl taurine sodium, tetradecene Sulfonates such as sodium sulfonate, alkyl sulfates such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, anionic surfactants such as α-olefin sulfonate; alkylamine Examples include cationic surfactants such as salts, alkyl quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, etc.), alkylpyridinium salts (cetylpyridinium chloride, cetylpyridinium bromide, etc.), etc. That. Preferred surfactants include polyoxyethylene (POE) -polyoxypropylene (POP) block copolymers (for example, poloxamer 407, poloxamer 235, poloxamer 188, etc.), monolauric acid POE (20) sorbitan (polysorbate 20), mono Oleic acid POE
(20) POE sorbitan fatty acid esters such as sorbitan (polysorbate 80), POE (60) POE hydrogenated castor oil such as castor oil, POE (9)
POE alkyl ethers such as lauryl ether, P
OE (20) POP (4) PO such as cetyl ether
Nonionic surfactants such as E.POP alkyl ethers and POE alkylphenyl ethers such as POE (10) nonylphenyl ether. The numbers in parentheses indicate the number of added moles.

The ophthalmic composition of the present invention may contain various components (including pharmacologically active ingredients and physiologically active ingredients) in combination as long as the effects of the present invention are not impaired. The type of such a component is not particularly limited, and for example, a decongestant component,
Ocular muscle modulator component, α-adrenergic agonist component, anti-inflammatory drug component, astringent drug component, antibacterial drug or bactericidal drug component, vitamins, amino acids, saccharides, local anesthetic drug component, steroid component, antihistamine drug component or Examples thereof include antiallergic drug components, cellulose or derivatives thereof or salts thereof, polysaccharides or derivatives thereof, and the like. Examples of suitable components in the present invention include the following components.

Decongestant components: Epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and salts thereof Ophthalmic muscle modulator components: Cholinesterase inhibitors having an active center similar to acetylcholine, for example, neostigmine methylsulfate and the like. Α-adrenergic agonist components such as quaternary ammonium compounds and salts thereof: for example, imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-
Phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and pharmaceutically or physiologically acceptable salts thereof (for example,
Anti-inflammatory drug components such as inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate, etc .: celecoxib ,
Astringent drug components such as rofecoxib, indomethacin, diclofenac, pranoprofen, piroxicam, meloxicam, lysozyme, allantoin, and pharmacologically acceptable salts (eg, diclofenac sodium, lysozyme chloride): zinc and Their salts (eg zinc sulphate,
Zinc lactate) and other antihistamine or antiallergic drug components: for example, diphenhydramine, iproheptin,
Ketotifen, clemastine, azelastine, olopatadine, tranilast, amlexanox, mequitazine,
Loratadine, fexofenadine, cetirizine (ce
antibacterial or bactericidal component such as pharmacologically acceptable salts (eg, diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, clemastine fumarate, azelastine hydrochloride, olopatadine hydrochloride, etc.), such as tirizine), ibudilast, suplatast, pemirolast. For example, sulfonamides (eg, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.), acrinol, 4th Quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium), and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, etc.) ), Alkylpolyaminoethylglycine, new quinolone agents (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), biguanides (polyhexamethylene biguanide, chlorhexidine or its salts, etc.), berberine or its salts , Polydronium chloride, Glokil
l (trade name, for example Glokill PQ, manufactured by Rhodia), polydiallyldimethylammonium chloride,
Poly [oxyethylene (dimethyliminio) ethylene-
(Dimethyliminio) ethylenedichloride], parabens (methyl benzoate, ethyl aminobenzoate, etc.), and other vitamins: For example, vitamins A [eg, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and its drug] Physically acceptable salts (eg, retinol acetate, retinol palmitate, etc.), vitamins B [eg, thiamine, thiamine disulfide, dicetiamine, octothiamine, shicothiamine, bis-ibutyamine, bisbentiamine, prosultiamine] , Benfotiamine, fursultiamine,
Riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinamide, nicotinic alcohol, pantothenic acid, panthenol, biotin, Choline,
Inositol and its pharmacologically acceptable salts thereof (for example, thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, riboflavin butyrate, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, pyridoxal phosphate, pyridoxal calcium phosphate) , Hydroxocobalamin hydrochloride, hydroxocobalamin acetate, calcium pantothenate, sodium pantothenate, etc.], vitamin C [ascorbic acid and its derivatives, erythorbic acid and its derivatives and pharmacologically acceptable salts thereof (eg, ascorbine) Acid salts, sodium erythorbate, etc.), vitamin C [ascorbic acid and its derivatives,
Erythorbic acid and its derivatives and pharmacologically acceptable salts thereof (for example, sodium ascorbate, sodium erythorbate, etc.), vitamin Ds [for example, ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxy] Cholecalciferol, dihydrotachysterol and pharmacologically acceptable salts thereof, etc.], vitamin E [eg tocopherol and its derivatives, ubiquinone derivatives and pharmacologically acceptable salts thereof (tocopherol acetate, nicotine) Acid tocopherol, tocopherol succinate, calcium tocopherol succinate, etc.), and other vitamins [eg, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, hesperitin Zin and its pharmacologically acceptable salts (carnitine chloride, etc.)] Amino acids: For example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, Glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylysine, glycylglycine, aminoethylsulfonic acid (taurine)
And pharmaceutically acceptable salts thereof (eg potassium aspartate, magnesium aspartate, cysteine hydrochloride etc.), saccharides: monosaccharides (eg glucose etc.), disaccharides (eg trehalose, lactose, fructose etc.), oligos Sugars (eg, lactulose, raffinose, pullulan, etc.), cellulose or derivatives thereof (eg, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, etc.), polymeric sugars (eg, chondroitin sulfate,
Hyaluronic acid, etc. and pharmacologically acceptable salts thereof (eg, sodium chondroitin sulfate, sodium hyaluronate, etc.), sugar alcohols (eg, mannitol, xylitol, sorbitol, etc.), local anesthetic ingredients: lidocaine, oxyprocaine, etc. , Dipcaine, procaine, ethyl aminobenzoate, meprilukaine, and their salts (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) Steroid components: hydrocortisone, prednisolone,
And anti-histamine or anti-allergic drug components such as salts thereof: for example, chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglic acid, tranilast, amlexanox, mequitazine, ororatadine, loratazine.
ne), fexofenadin
e), cetirizine, ibudilast, suplatast, pemirolast, and pharmacologically acceptable salts (eg chlorpheniramine maleate,
Diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, sodium cromoglycate, etc.) cellulose or its derivatives or salts thereof: methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxy Polypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, cellulose and other polysaccharides or derivatives thereof: gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac butter, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein. , Agar,
Alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoids, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate and other Ingredients: polyvinyl alcohol (fully or partially saponified), polyvinyl pyrrolidone, etc.

The content of these components can be selected according to the kind of the preparation, the kind of the active ingredient, etc., and is, for example, 0.0001 to 30%, preferably 0.001 to the whole preparation.
It can be selected from the range of about 1 to 10%.

More specifically, in the ophthalmic composition,
The content of each component is as follows, for example.

Decongestant component (vasoconstrictor or sympathomimetic): For example, 0.0001 to 0.5%, preferably 0.0005 to 0.3%, more preferably 0.0.
01-0.1% Ocular muscle modulator component: For example, 0.0001-0.5%, preferably 0.001-0.1% Anti-inflammatory drug component or astringent drug component: For example, 0.0001
-10%, preferably 0.0001-5% Antihistamine drug component or antiallergic drug component: For example, 0.0001-10%, preferably 0.001-5
% Antibacterial or bactericidal component: eg 0.001-10
%, Preferably 0.01 to 10% Vitamins: eg 0.0001 to 1%, preferably 0.0001 to 0.5% Amino acids: eg 0.0001 to 10%, preferably 0.1. 001 to 3% saccharides: for example, 0.0001 to 5%, preferably 0.0
01-5%, more preferably 0.01-2% Local anesthetic component: for example, 0.001-1%, preferably 0.01-1% Cellulose or its derivative or salt thereof: For example,
0.001-5%, preferably 0.01-1% Polysaccharides or derivatives thereof: for example 0.0001-2%,
Preferably 0.01 to 2%, more preferably 0.01
˜1% Polyvinylpyrrolidone, polyvinyl alcohol: for example, 0.001 to 10%, preferably 0.001 to 5
%, More preferably 0.01 to 3%.

The form of the ophthalmic composition of the present invention is not particularly limited as long as the effects of the invention are not impaired, and various carriers (aqueous carrier, hydrophilic carrier, oil carrier, liquid carrier, etc.) are used. It can be formulated in combination with.

In the present invention, if necessary, various components and additives are arbitrarily selected or used in combination in accordance with ordinary methods according to the application and form, as long as the effects of the invention are not impaired. It is possible. For example, thickeners, surfactants, preservatives, bactericides, antibacterial agents, pH adjusters, isotonic agents, inorganic salts, chelating agents, buffers, solubilizing agents, suspending agents, emulsifiers, antioxidants. Examples include various additives such as agents and fragrances. Among them, the solubilizing agent is a compounding component suitable for improving the solubility of the xanthines of the present invention in a liquid formulation and forming a stable liquid formulation. Examples of such solubilizing agents include benzoic acid, citric acid, aminoisobutanol, taurine and salts thereof, surfactants, and polyhydric alcohols such as propylene glycol.

The typical components used in the ophthalmic composition of the present invention are exemplified below, but the components are not limited to these components.

Thickeners: For example, polysaccharides or derivatives thereof (gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac butter, quince seed, darman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin. , Dextran, carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoids, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, etc.), ceramide, cellulose Derivatives (methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethyl Cellulose, carboxyethyl cellulose, cellulose), polyvinyl alcohol (completely or partially saponified), polyvinyl pyrrolidone,
Saccharides such as macrogol, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid, and pharmacologically acceptable salts thereof: for example, glucose, fructose, galactose, mannose, ribose, Ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol, etc., and their pharmacologically acceptable salts, etc.

Preservatives, bactericides or antibacterial agents: for example, paraoxybenzoic acid ester (methyl paraoxybenzoate,
Ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), acrinol,
Methylrosaniline chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, chlorhexidine, polyhexamethylene biguanide, alkylpolyaminoethylglycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, zirconium phosphate Of silver, zinc, zinc oxide, etc., silver zinc aluminosilicate, thimerosal, dehydroacetic acid, chlorxylenol, chlorophene, resorcin, thymol, hinokitiol, sulfamine, lactoferrin, triclosan, 8-hydroxyquinoline,
Undecylenic acid, caprylic acid, propionic acid, benzoic acid, propionic acid, sorbic acid, potassium sorbate,
Sodium sorbate, triclocarban sorbate,
Halocarban, thiabendazole, polymyxin B, 5
-Chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, polylysine, hydrogen peroxide, polydronium chloride, Gloki
ll (trade name eg Glokill PQ, manufactured by Rhodia), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethylenedichloride], etc.,
And pH adjusters such as pharmaceutically acceptable salts thereof: for example, inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (lactic acid, acetic acid, citric acid, tartaric acid, malic acid, Succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, aspartic acid,
Glutamic acid, aminoethylsulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic bases (sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, etc.), organic bases (monoethanolamine) , Triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.), borax, and pharmacologically acceptable salts thereof, etc. Isotonizing agents: for example, polyhydric alcohols such as glycerin and propylene glycol, sugars ( Butter sugar, mannitol, sorbitol, etc.) inorganic salts such as sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride,
Chelating agents such as magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium thiosulfate, and sodium acetate: For example, edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDD)
A), diethylenetriaminepentaacetic acid (DTPA), N-
(2-hydroxyethyl) ethylenediaminetriacetic acid (H
EDTA), N- (2-hydroxyethyl) iminodiacetic acid (HIDA), citric acid, tartaric acid, phosphoric acids (polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid), succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid,
Perfume or cooling agent such as 1-hydroxyethane-1,1-diphosphonic acid or salts thereof: for example, menthol, camphor, borneol, geraniol, eucalyptus oil, bergamot oil, fennel oil, peppermint oil, cinnamon oil, rose oil, Such as peppermint oil.

The ophthalmic composition of the present invention may optionally contain
It is necessary to adjust the pH and / or osmotic pressure within the range that is acceptable to the living body. The pH is usually pH 4.0 to 9.0,
It is preferably 5.0 to 8.5, and particularly preferably 5.5.
It is 8.5. The osmotic pressure is 100 to 1200 mOsm,
Preferably 100 to 600 mOsm, particularly preferably 1
It is about 50 to 400 mOsm, and the osmotic pressure ratio to the physiological saline is usually 0.3 to 4.1, preferably 0.3.
To 2.1, particularly preferably 0.5 to 1.4.
The pH can be adjusted using a buffering agent, the pH adjusting agent, the tonicity adjusting agent, the inorganic salt, or the like.

The pH of the ophthalmic composition of the present invention can be adjusted by using a buffering agent in order to further improve the feeling of use. Since the quality of the ophthalmic composition using the buffer is stably maintained, the ophthalmic composition having an excellent feeling in use can be stably retained for a long period of time, and the user can use the ophthalmic composition multiple times. It is useful for continuous use. Examples of such a buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, aspartate and the like. Preferred buffers are borate buffers, phosphate buffers, carbonate buffers and citrate buffers. Particularly preferred buffering agents are borate buffers or phosphate buffers. Examples of the borate buffer include boric acid, borate salts such as alkali metal borate and alkaline earth metal borate, or a combination of boric acid and borate. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphates and alkaline earth metal phosphates, or a combination of phosphoric acid and a phosphate. In addition, a borate or a hydrate of a phosphate may be used as the borate buffer or the phosphate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or salts thereof (sodium hydrogen carbonate, sodium carbonate, etc.), citric acid or salts thereof (sodium citrate, potassium citrate, etc.). When a borate buffer or a phosphate buffer is used as the buffer, the concentration of these buffers in the ophthalmic composition of the present invention is, for example, 0.0001 to 10.0% by weight.
It is a degree.

The ophthalmic composition of the present invention can be produced by a known method. The composition can be prepared by mixing the base and each component. Furthermore, if necessary, the osmotic pressure and pH can be adjusted to a predetermined level, and a filtration sterilization treatment step in a sterile environment, a container filling step, and the like can be added.

[0039]

INDUSTRIAL APPLICABILITY The ophthalmic composition of the present invention, such as cromoglycic acid, acitazanolast, levocabastine, emedastine, epsilon-aminocaproic acid, berberine, glycyrrhizic acid or a salt thereof, is not harmful to the user when applied to the ocular mucosa. It is characterized in that it contains a compound which gives a pleasant sensation and eventually reduces compliance, and xanthines. Then, by blending these components having an unpleasant feeling of use with xanthines, it is possible to improve the unpleasant taste such as unpleasant taste and irritation that occurs when the ophthalmic composition is applied to the ocular mucosa. , The user's compliance can be improved. Furthermore, the ophthalmic composition of the present invention is an ophthalmic composition that is directly applied to the eye mucous membrane such as eye drops, eyewash, contact lens mounting solution, contact lens solution (cleansing solution, preservative solution, sterilizing solution, multipurpose solution). It is useful as a thing.

[0040]

EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

Examples 1 to 47 The ingredients of the formulations shown in Tables 1 to 7 below were dissolved in purified water to make the total amount 100 mL, and sterile filtered to prepare eye drops, eye washes, and liquids for contact lenses. did. Among the blended components, as the concentrated benzalkonium chloride solution 50 and sodium edetate, reagents conforming to the Japanese Pharmacopoeia were used.

[0042]

[Table 1]

[0043]

[Table 2]

[0044]

[Table 3]

[0045]

[Table 4]

[0046]

[Table 5]

[0047]

[Table 6]

[0048]

[Table 7]

[0049]

[Table 8]

[0050]

[0051]

[0052]

[0053]

[Test Example] Test Example Usability test The prescription components shown in Tables 8 to 14 below were dissolved in sterile purified water to a total volume of 100 ml, sterile filtered and filled in a container to prepare an eye drop.

Sodium cromoglycate, acitazanolast hydrate, levocabastine hydrochloride, emedastine fumarate or epsilon described in Tables 8 to 12 below.
Each eye drop containing aminocaproic acid was tested for eye irritation when instilled. The test was performed by instilling 2 drops of each test solution on 10 specialized panelists, and the intensity of pain or irritation felt at the time of instillation was expressed by a score, and the average value thereof was calculated. The score was 2 points when feeling pain or irritation, 1 point when slightly feeling pain or irritation, and 0 point when neither pain nor irritation was felt. The results are shown in Tables 8 to 12.

Ten dedicated panelists tested the unpleasant taste of each of the eye drops containing dipotassium glycyrrhizinate or berberine sulfate shown in Tables 13 to 14 below. The test is performed by instilling 2 drops of each test solution, and after dipping the potassium glycyrrhizinate, the proportion of those who felt an unpleasant taste such as "accumulation", "sweetness" or "too sweet" was calculated, and sulfuric acid was calculated. For berberine, the percentage of those who felt an unpleasant taste such as "aguri", "astringency", and "bitterness" after instillation was calculated. The results are shown in Tables 13 to 14.

[0056]

[Table 9]

[0057]

[Table 10]

[0058]

[Table 11]

[0059]

[Table 12]

[0060]

[Table 13]

[0061]

[Table 14]

[0062]

[Table 15]

As a result of these tests, by adding caffeine (anhydrous caffeine), which is a xanthine compound, sodium cromoglycate, acitazanolast hydrate, levocabastine hydrochloride, emedastine fumarate or epsilon-aminocaproic acid was contained. It was shown that unpleasant eye irritation or eye pain when applying the eye drops was suppressed and relieved. Further, when 1 part by weight of sodium cromoglycate, acitazanolast hydrate, emedastine fumarate or epsilon-aminocaproic acid is mixed with xanthines in a proportion of 0.1 parts by weight or more, unpleasant eye irritation or The effect of improving eye pain was remarkable. On the other hand, with levocabastine hydrochloride, when xanthines were mixed in a proportion of 4 parts by weight or more to 1 part by weight of levocabastine hydrochloride, the effect of improving unpleasant eye irritation or eye pain was remarkable.

It was also shown that the addition of caffeine (anhydrous caffeine), which is a xanthine compound, improved the unpleasant taste when injecting dipotassium glycyrrhizinate or berberine sulfate. Then, when xanthines were mixed in a proportion of 0.1 parts by weight or more with respect to 1 part by weight of dipotassium glycyrrhizinate or berberine sulfate, the effect of improving unpleasant taste was remarkable.

Therefore, an ophthalmic medicine in which the xanthines such as caffeine contain sodium cromoglycate, acitazanolast hydrate, levocabastine hydrochloride, emedastine fumarate, epsilon-aminocaproic acid, dipotassium glycyrrhizinate or berberine sulfate. It was confirmed that the composition exerts an excellent effect in improving the unpleasant feeling of use.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/522 A61K 31/522 31/551 31/551 31/704 31/704 A61P 27/02 A61P 27 / 02 F term (reference) 4C086 AA02 BA08 BC21 BC54 BC62 CA01 CB07 EA10 GA07 MA02 MA04 MA58 NA09 ZA33 4C206 AA02 FA44 MA02 MA04 MA17 MA78 NA09 ZA33

Claims (4)

[Claims] 1. A) Formula (1): (Wherein R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group) or a pharmaceutically acceptable compound thereof. At least one compound selected from among salts thereof, and B) selected from cromoglycic acid, acitazanolast, levocabastine, emedastine, epsilon-aminocaproic acid, berberine, glycyrrhizic acid or a pharmaceutically acceptable salt thereof. An ophthalmic composition comprising at least one compound described above. 2. The ophthalmic composition according to claim 1, wherein the compound of formula (1) is caffeine, pentoxifylline, theophylline, diprophylline, theobromine, proxyfilin. 3. 1 part by weight of at least one compound selected from cromoglycic acid, acitazanolast, emedastine, epsilon-aminocaproic acid, berberine, glycyrrhizic acid or a pharmacologically acceptable salt thereof, A compound represented by the formula (1) or a salt thereof is added to
The ophthalmic composition according to claim 1 or 2, which is blended in a proportion of 1 part by weight or more. 4. The compound represented by the formula (1) or a salt thereof in an amount of 4 parts by weight or more based on 1 part by weight of levocabastine or a pharmacologically acceptable salt thereof. The ophthalmic composition according to.